How a bloodless fish could change resuscitation

We all know fishermen love to tell tales, but when biologist Ditlef Rustad caught a clear fish off the coast of Antarctica in 1928 he really pushed it. I can only imagine the looks on his friends faces when he told them he cut it open and its blood ran clear. The thing was, this wasn’t a fisherman’s tale, this bloodless fish actually exists. 1

The crocodile icefish as Rustad called it, thrived so well that it was originally thought to have developed its lack of hemoglobin(Hb), myoglobin(Mb) and RBC’s as an evolutionary advantage due to the cold, oxygen dense waters around the antarctic circle. Follow up genetic testing though has shown that it was more likely the victim of a series of unfortunate genetic mutations 2 that caused it to lose these traits so often deemed necessary for life. Yet it survived, and the mechanism by which it survived may start to sound familiar to human physiology buffs.

When the icefish lost it’s Hb and Mb, it lost its oxygen carrying and storage capacity. This led to hypoxia and subsequent production of NO by eNOS. This led to a compensatory vasodilation which reduced vascular resistance and allowed the thinner blood to traverse the circulation faster. By increasing the speed of circulation the fish was able to compensate for a lack of oxygen carrying capacity. Where the normal RBC carrying cousin of the icefish expends 5% of it’s resting metabolic rate on it’s heartbeat, the RBC free version expends a whopping 22%. Further proving this was not an advantageous mutation. This was further augmented by the fact that Hb and Mb are both descended from bacterial versions of themselves that were used to digest NO into nitrate for food, so without Hb and Mb, NO was able to stick around longer and the effect eventually became permanent. I’m not going to get into the rest of the effects that future generations of the fish eventually developed to adapt to its RBC free lifestyle like more mitochondria or increased VEGF to make more blood vessels. I just want to talk about that initial fish #1 that survived.

You see, patients present to us in the ED with something not too dis-similar than what happened to icefish #1. Whether it be severe hypovolemia due to blood loss or sepsis, regardless of the type of shock, it is defined as hypoperfusion. The gas simply isn’t being exchanged at the tissue level the way it should be. We understand the problem to be a lack of oxygen getting to the tissue, which is why the River’s protocol for sepsis said to insert an ScVO2 sensor and if it was low, give RBC’s. But this was recently proven about seven times over to not be helpful. So now we’re back to the mainstay of administering fluids to increase blood pressure, and when that doesn’t work we administer vasoconstrictors. We’ve got to get that blood pressure up, right? Well, that’s where I think we’re going wrong.

When the icefish had a sudden, massive case of hypoperfusion, its response wasn’t profound vasoconstriction. It was actually vasodilation, and that saved its life. What do we often see, and then attempt to correct with vasoconstrictors in sepsis? Profound vasodilation. That’s probably because it’s easy for us to measure blood pressure, hard for us to measure blood flow, and even harder for us to measure perfusion. So we give drugs that make the number we’re measuring look better. But instead of actually making the patient better, we’re just altering our measurement! Going back to simple physics, ohm’s law (V=IR) tells us that pressure is a function of resistance at a given flow, so when we increase our vascular resistance we will be decreasing flow even if the blood pressure never changes! And what about that ScVO2 measurement? Well, the River’s protocol said to increase low readings with pRBC transfusions. But we need to remember why we got low ScVO2 readings in the first place. If we remember the Fick principle we can measure blood flow by measuring a difference in arterial O2 and venous O2 as long as we know the O2 consumption. Well it just so happens that arterial O2 is normally relatively fixed, as is O2 consumption in a resting patient. So a low ScVO2 indicates low blood flow, not low blood oxygen. So when we give those pRBC’s all we were actually doing was increasing arterial O2 by increasing oxygen carrying capacity. Once again we were altering the measurement, not fixing the problem. If we use ScVO2 correctly to measure the adequacy of blood flow, and not oxygen carrying capacity, it might still be a pretty valuable test.

Just like the icefish, the normal physiologic response to hypoperfusion in the human body is to release NO which dilates the local arterioles and to some extent the capillary bed as well, this decreases resistance and increases blood flow. When the area of hypoperfusion is large or global, the cardiac output quickly becomes insufficient to sustain the necessary blood flow to support such dilation and this leads to worsening shock. This is the point where we get called in. Large fluid administrations may help support cardiac function by increasing preload, reducing blood viscosity and augmenting the frank-starling effect that occurs when you stretch those myocardial titin springs, but inotropes may still be necessary. This is where I will differ from the mainstream, all vasoconstricting inotropes (norepinephrine, dopamine, etc.) have been shown to reduce outcomes. It’s possible something more like milrinone would be helpful, but I think the best one is probably the Ca++ sensitizing agent levosimendan 3, but it isn’t FDA approved yet. I’ll talk about that very interesting drug more in a later article. Regardless of which inotrope you consider, the human heart is likely not going to be able to acutely increase its output that much for very long, which should probably lead us to think about augmenting flow mechanically with something like the Impella, other LVAD’s or ECMO.

Unfortunately this is mostly conjecture currently as there is only scant research into this and almost none of it is outcomes based. The physiology however is simple, and it says we’re probably doing this wrong. We probably shouldn’t just let these people sit in the ICU on vasoconstricting drips that squeeze everything off trying to keep up a blood pressure and then expect them to do well, it’s not gonna happen. We would be better served to remember that the problem is not low blood pressure, it’s low blood flow and we must find ways to aggressively increase their blood flow until it meets tissue oxygen demand. We should stop looking to increase blood pressure numbers with vasoconstrictors and stop looking at vasodilatory sepsis as something that needs to be remedied. That NO mediated decrease in vascular resistance is keeping them perfusing and is probably something we need to support. Remember, there’s a bloodless fish out there to prove it.

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3 thoughts on “How a bloodless fish could change resuscitation”

Hey yall just read the bloodless fish stuff eatin it like east texas butter………So in my goofy uneducated mind help me get the potential application. How would we then theoretically keep dying folks alive until we could get flow to meet metabolic needs. love the conceptualized view….Just a dense ole worn out paramedic……..
Would we have some super mechanical augmentation as a gap therapy, ECMO seems a bit for a rural hospital setting what do yall see as the stop gap measure?????/Love it yall make me proud!
chuck

Hey Chuck! Hard to say yet, ECMO is all the rage right now but until we find a easier way to mechanically augment flow it’s going to be difficult to move beyond ECMO. Impella is an option as well but requires essentially a cath lab so that’s even more resource intensive. The point I’m seeing with the bloodless fish is that the idea that blood pressure and hemoglobin are important to resuscitative perfusion is an oversimplification of the problem which has created a misdirection of our efforts. Dr Rivers EGDT for sepsis called for transfusions to correct low SCVO2 which was recently found to be unhelpful. It’s no surprise though when you realize that SCVO2 was really serving as a marker of perfusion via the Fick principal and transfusing them meant you were changing the oxygen consumption constant. In essence you were altering your test to give you better numbers rather than actually improving the patients physiology. It ‘may’ be helpful (very little evidence, mostly theory at this point) to supplement the patient’s adenosine and NO levels even in the face of low SVR in addition to supplementing their volume. This would lead to supraphysiologic cardiac output which could cause an MI and is where mechanical flow augmentation comes in. We would also need to identify if maintaining a lower MAP of say 40mmHg but at a supraphysiologic flow is damaging to the kidneys. We just don’t know that yet that I’m aware of. The point is, we now that staying in the ICU on pressors doesn’t work, and giving transfusions to SCVO2 in sepsis doesn’t either. So when looking for the next treatment avenue, this makes the most sense to me.

Awesome Jason,
Thanks for the info brother. I was actually looking for some more primitive form of flow( augmented super CPR) of some sort in order for the flow concept to buy the minutes necessary to reach a facility capable of doing the ECMO etc……… the resq-cpr device is actually pretty impressive at producing BP and ETCO2 obviously limited by fatigue and human error……………Thanks for the info my friend always a JOY!!!!!!!!
kEEP ME LEARNING MAN I DONT WANT TO BE THAT OLD MEDIC WHO USED TOBE!

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